XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation

Yabal, Monica; Müller, Nicole; Adler, Heiko; Knies, Nathalie; Gross, Christina J.; Damgaard, Rune Busk; Kanegane, Hirokazu; Ringelhan, Marc; Kaufmann, Thomas; Heikenwächter, Mathias; Strasser, Andreas; Gross, Olaf; Ruland, Jürgen; Peschel, Christian; Gyrd-Hansen, Mads; Jost, Philipp J. (2014). XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation. Cell reports, 7(6), pp. 1795-1808. Cell Press 10.1016/j.celrep.2014.05.008

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X-linked inhibitor of apoptosis protein (XIAP) has been identified as a potent regulator of innate immune responses, and loss-of-function mutations in XIAP cause the development of the X-linked lymphoproliferative syndrome type 2 (XLP-2) in humans. Using gene-targeted mice, we show that loss of XIAP or deletion of its RING domain lead to excessive cell death and IL-1β secretion from dendritic cells triggered by diverse Toll-like receptor stimuli. Aberrant IL-1β secretion is TNF dependent and requires RIP3 but is independent of cIAP1/cIAP2. The observed cell death also requires TNF and RIP3 but proceeds independently of caspase-1/caspase-11 or caspase-8 function. Loss of XIAP results in aberrantly elevated ubiquitylation of RIP1 outside of TNFR complex I. Virally infected Xiap−/− mice present with symptoms reminiscent of XLP-2. Our data show that XIAP controls RIP3-dependent cell death and IL-1β secretion in response to TNF, which might contribute to hyperinflammation in patients with XLP-2.

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